KIT
1 variant(s) documented across Systemic Mastocytosis
Variants
| Variant | Type | Frequency in disease | Significance | Also found in |
|---|---|---|---|---|
| D816V (c.2468A>T) | somatic | >90% of adult SM (by sensitive assays) | The central driver mutation of systemic mastocytosis. Causes constitutive ligand-independent activation of the KIT receptor tyrosine kinase, driving mast cell proliferation, survival, and activation. Arises in early hematopoietic stem/progenitor cells. | Gastrointestinal stromal tumors (GIST) (~5% (mostly other KIT mutations)); Core binding factor AML (~25-30%) |
Clinical implications
D816V (c.2468A>T)
WHO minor diagnostic criterion. Target of midostaurin and avapritinib. Confers resistance to imatinib. VAF >=10% is a B-finding indicating high MC burden.
Testing: allele-specific quantitative PCR, digital PCR, next-generation sequencing, Sanger sequencing (low sensitivity)
Related molecules in pathway
Central oncogenic driver — mutated receptor tyrosine kinase — Constitutively activated (D816V mutation)
Normal KIT ligand — bypassed in D816V+ disease — Normal
Related hypotheses
KIT D816V is necessary and sufficient as the sole driver of indolent SM, while advanced SM requires cooperating mutations in a multi-hit model
75The STAT5-PI3K-AKT-mTOR axis is the dominant oncogenic signaling cascade downstream of KIT D816V and the primary target for therapeutic intervention
70Deep molecular responses (KIT D816V undetectable) achieved by selective KIT inhibitors can alter the natural history of SM and prevent progression
50Hereditary alpha-tryptasemia (HαT) modifies SM phenotype, increasing mediator symptoms and anaphylaxis risk independent of mast cell burden
40